Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine's Antidepressant Action.
Hydroxynorketamine: Implications for the NMDA Receptor Hypothesis of Ketamine's Antidepressant Action.
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DOI：
10.1177/2470547017743511
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发表时间：
2017-01-01
期刊：
影响因子：
--
通讯作者：
Phillips, Anthony G
中科院分区：
文献类型：
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作者：
Aleksandrova, Lily R;Wang, Yu Tian;Phillips, Anthony G
氯胺酮独特的抗抑郁作用的流行假设涉及N-甲基-d-天冬氨酸受体（NMDAR）抑制依赖性增强α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的传递，激活细胞内信号传导途径和增加突触发生。然而，最近Zanos等人的一项开创性研究直接挑战了氯胺酮的NMDAR假设，声称活性氯胺酮代谢物（2 R，6 R）-羟基去甲氯胺酮（不具有NMDAR结合特性或其母体化合物的关键副作用）对于氯胺酮在啮齿动物中的抗抑郁作用是必要且充分的。然而，在这些令人鼓舞的初步发现之后，一项临床前研究未能复制（2 R，6 R）-羟基去甲氯胺酮（HNK）的抗抑郁作用，而其他研究则质疑代谢物对氯胺酮治疗作用的贡献或反对拒绝氯胺酮作用的NMDAR假设。鉴于这些潜在的范式转变，但极具争议的，调查结果，本次审查将总结和批判性地评估的证据和反对的NMDA受体假说氯胺酮的行动，特别侧重于（2 R，6 R）-HNK和它的发现的影响，了解氯胺酮的作用机制，在抑郁症。最终，揭示氯胺酮和可能的（2 R，6 R）-HNK的治疗作用的分子机制，将有助于开发新的和更有效的抗抑郁药，迫切需要解决一个主要的公共卫生问题，并可能保持治疗其他压力相关的精神病理学，包括双相情感障碍，创伤后应激障碍和自杀。
The prevailing hypothesis of ketamine's unique antidepressant effects implicates N-methyl-d-aspartate receptor (NMDAR) inhibition-dependent enhancement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated transmission, activation of intracellular signalling pathways and increased synaptogenesis. Recently, however, a seminal study by Zanos et al. directly challenged the NMDAR hypothesis of ketamine with the claim that an active ketamine metabolite, (2R,6R)-hydroxynorketamine, devoid of NMDAR binding properties or key side effects of its parent compound, is both necessary and sufficient for ketamine's antidepressant effects in rodents. However, following these encouraging initial findings, one preclin-ical study failed to replicate the antidepressant effects of (2R,6R)-hydroxynorketamine (HNK), while others have questioned the metabolite's contribution to ketamine's therapeutic effects or argued against rejecting the NMDAR hypothesis of ketamine action. In light of these potentially paradigm-shifting, but highly controversial, findings, this review will summarise and critically evaluate the evidence for and against the NMDA receptor hypothesis of ketamine action, with a particular focus on (2R,6R)-HNK and the implications of its discovery for understanding ketamine's mechanism of action in depression. Ultimately, uncovering the molecular mechanisms underlying the therapeutic effects of ketamine and possibly (2R,6R)-HNK, will aid the development of novel and more efficacious antidepressant agents so urgently needed to address a major public health concern, and could hold potential for the treatment of other stress-related psychopathologies, including bipolar disorder, post-traumatic stress disorder and suicidality.